Process for preparing N-benzyl indoles

ABSTRACT

This invention relates to a method of making N-benzyl indoles, and to intermediates for use in the method, and to certain substantially optically pure N-benzyl indoles obtained by the method.

This application is a divisional of Ser. No. 09/103,858, filed Jun. 24,1998 now U.S. Pat. No. 6,160,120, which is a divisional of Ser. No.08/753,024, filed Nov. 19, 1996 now U.S. Pat. No. 5,807,866.

This invention relates to a process for the preparation of N-benzylindoles, and to intermediates for use in the 5 process, and to certainsubstantially optically pure N-benzyl indoles obtained by the process.

EP-A-0469833 discloses a class of N-benzyl indoles including compoundsof the formula

in which R¹ is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitrile,optionally protected carboxy, optionally protected tetrazolyl,trihalomethyl, hydroxy-C₁₋₄ alkyl, aldehyde, —CH₂Z, —CH═CH—Z or —CH₂CH₂Zwhere Z is optionally protected carboxy or optionally protectedtetrazolyl; R² is halo, nitrile, an optionally protected acid group or—CONR⁷R⁸ where R⁷ and R⁸ are hydrogen or C₁₋₄ alkyl; R⁴ is C₂₋₄ alkyl,or C₂₋₄ alkyl substituted by —CONR⁷R⁸ or an optionally protected acidgroup; R⁵ is

where W is —CH═CH—, —CH═N—, —N═CH—, —O— or —S—, R⁹ is hydrogen, halo,C₁₋₄ alkyl, C₁₋₄ alkoxy or trihalomethyl, and R¹⁰ is hydrogen, C₁₋₄alkyl, C₃₋₆ alkenyl, C₃₋₆ cycloalkyl or C₁₋₄ alkyl-C₃₋₆ cycloalkyl; R⁶is hydrogen or C₁₋₄ alkyl; X is —O—(CH₂)_(n)CR¹¹R¹²—, —CR¹¹R¹²—,—CR¹¹R¹².(CH₂)_(n)—CR¹³R¹⁴— or —CR¹¹═CR¹²— where R¹¹, R¹², R¹³ and R¹⁴are each hydrogen or C₁₋₄ alkyl, and n is 0, 1 or 2; and Y is—O—CR¹⁵R¹⁶—, —CR¹⁵═CR¹⁶— or —CR¹⁵R¹⁶. CR¹⁷R¹⁸— where R¹⁵, R¹⁶, R¹⁷ andR¹⁸ are each hydrogen or C₁₋₄ alkyl; and salts thereof.

Amongst the compounds disclosed in EP-A-0469833, one particularlyimportant compound has the formula

The compounds disclosed in EP-A-0469883 are leukotriene antagonists, andare accordingly indicated for therapeutic use in the treatment ofdiseases in which leukotrienes are implicated. These include allergicreactions of the pulmonary system in which leukotrienes are thought tobe causal mediators of bronchospasm, for example, in allergic lungdisorders such as extrinsic asthma and industrial asthmas such asFarmers Lung, and in other inflanmmatory disorders, for example,associated with acute or chronic infectious diseases such as allergicskin diseases, ectopic and atopic eczemas, psoriasis, contacthypersensitivity and angioneurotic oedema, bronchitis and cysticfibrosis and rheumatic fever. The compounds disclosed in EP-A-0469833also have potential in the treatment of vascular diseases such as shockand ischaemic heart diseases for example coronary artery disease andmyocardial infarction, cerebrovascular diseases, and renal diseases suchas renal ischaemia.

EP-A-0469833 discloses certain processes for the preparation of theN-benzyl indoles disclosed therein. However, the overall yield which isobtainable using the processes disclosed in EP-A-0469833 is not high,and the compounds are generally obtained in the form of racemates. Inmany cases, including the case of the compound of Formula (I′) above,separation of enantiomers by conventional techniques, such as byreaction with a chiral amine followed by fractional recrystallisation,or separation on a chiral chromatographic support has been found to beextremely difficult. Nevertheless it has now been found that theS-enantiomer of the above compound of Formula (I′) is preferred andpharmacologically superior.

It is accordingly an object of the present invention to provide animproved process for preparing the N-benzyl indoles described above. Itis a further object of the invention to provide a process for preparingsuch N-benzyl indoles in the form of their substantially pureenantiomers.

According to one aspect of the present invention, there is provided aprocess which comprises the step of reacting an indoline compound of theformula

with epoxide compound of the formula

to form a compound of the formula

wherein R^(2a) is selected from the groups recited above for R², orR^(2a)—X— is a protected hydroxyl group, and wherein Z′ is a group offormula —Y—R⁵ as defined herein, or Z′ is a substituent that can beconverted into a group of formula —Y—R⁵. In any event, the group W mustbe chemically stable during the above-described reaction betweencompounds of formulae (II) and (III). Since the linking group Y ispreferably a vinyl group —CR¹⁵═CR¹⁵═CR¹⁶—, the substituent Z′ ispreferably a group that can be converted into a vinyl group by anolefination reaction. The preferred olefination method is palladium saltcatalyzed Heck coupling, as described further below, and accordingly Z′is preferably a leaving group such as Cl, Br, I, or a sulfonate such astrifluoromethylsulfonate or tosylate. The most preferred substituent Z′in this case is Br. Other preferred olefinations include Wittigreactions, in which case the substituent Z′ is preferably —CHO, orprotected —CHO, such as an acetal.

The reaction is carried out in a suitable solvent such as dryacetonitrile, and is preferably conducted in the presence of a Lewisacid catalyst such as magnesium perchlorate.

In the above formula (I), a halo substituent can be for example, chloro,bromo and fluoro and is preferably chloro. A C₁₋₄ alkyl group includesmethyl, ethyl, propyl, isopropyl, butyl and tert butyl and is preferablymethyl or ethyl, and a C₁₋₄ alkoxy group is one such alkyl groupattached through oxygen. A hydroxy C₁₋₄ alkyl group is ahydroxy-substituted C₁₋₄ alkyl group preferably of the formulaHO(CH₂)_(n)— where n is 1 to 4, a preferred example being hydroxymethyl.A C₃₋₆ cycloalkyl group includes for example cyclopropyl, cyclopentyland cyclohexyl, and is preferably cyclopropyl. The C₃₋₆ cycloalkyl groupcan be substituted by a C₁₋₄ alkyl. A C₂₋₆ alkenyl group is preferablypropenyl or isopropenyl. A trihalomethyl group is preferablytrifluoromethyl. An optionally substituted phenyl group is phenylitself, or phenyl substituted with one or more, preferably 1 to 3,substituents selected from C₁₋₄ alkyl, especially methyl, C₁₋₄ alkoxy,especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especiallychloro or fluoro, trihalomethyl, especially trifluoromethyl, carboxyC₁₋₄ alkoxy-carbonyl, and optionally protected tetrazolyl.

An acid group can be any acid group conventionally used inpharmaceutical chemistry and the term includes, for example tetrazolyl(1H-tetrazol-5-yl), carboxy (—COOH), phosphonate (—PO(OH)₂), sulphonate(—SO₂OH), acyl sulphonamido (—CONHSO₂R, where R is preferably C₁₋₄ alkylor optionally substituted phenyl) or cyanoguanidinyl (—NHC (NH₂)═NCN).Especially preferred examples are tetrazolyl and carboxy.

When R⁵ is the group

it comprises groups of the following type

and the quinolin-2-yl group is the most preferred.

R¹ is preferably hydrogen or halogen, and especially hydrogen, and whenit is other than hydrogen it is preferably attached to the indolenucleus at the 4-position.

The group R²—X— is attached to the indole nucleus at the 6- or7-position, and when X is —O—(CH₂)_(n)CR¹¹CR¹²— via the oxygen atom. R²is preferably an acid group especially tetrazolyl or carboxyl.

The R⁵ group is preferably quinolin-2-yl where the substituent R⁹, whichis preferably hydrogen or halo, is attached at the 7-position. The groupR⁵—Y— can be attached with the 2-, 3- or 4-positions to the phenylnucleus, and when R is —O—CR¹⁵R¹⁶— via the oxygen atom. R⁵—Y— ispreferably attached at the 3-position.

The R⁶ group is preferably hydrogen and when it is C₁₋₄ alkyl ispreferably attached at the 3-position.

The linking group X is preferably —O—CR¹¹R¹²— or CR¹¹R¹².CR¹³R¹⁴—, andR¹¹, R¹², R¹³ and R¹⁴ are preferably hydrogen. Linking group Y ispreferably of the formula —O—CR¹⁵R¹⁶, or —CR¹⁵═CR¹⁶—, and R¹⁵, R¹⁶, R¹⁷,and R¹⁸ are preferably hydrogen.

When acid substituents on the compound of formula (I) require protectionduring preparation they may be protected by conventional protectinggroups. Such protected compounds are included in the scope of theinvention, though the preferred compounds with optimum biologicalproperties are the unprotected compounds derived from them. A carboxycan be protected by protecting groups which include the well known esterforming groups used for the temporary protection of acidic carboxylicacid groups. Examples of such groups which have general use are readilyhydrolysable groups such as arylmethyl groups, haloalkyl groups,trialkylsilyl groups, alkyl groups, and alkenyl groups. A preferredprotected carboxy is C₁₋₄ alkoxy-carbonyl. Other carboxy protectinggroups are described by E. Haslam in Protective Groups in OrganicChemistry. Such protecting groups are also suitable for protectingphosphonate and sulphonate substituents. Furthermore, it is usuallynecessary to protect any tetrazolyl group during the process ofpreparation, and suitable and well known protecting groups for thispurpose include groups of the formula —CR′R″R′″ where R′ and R″ arehydrogen, C₁₋₄ alkyl or phenyl optionally substituted by one or moreelectron-donating groups such as, for example, C₁₋₄ alkoxy, and R′″ isphenyl optionally substituted by one or more electron donating groups.Preferred examples include trityl and benzhydryl.

When the acid substituent is tetrazolyl, then most preferred methodsinvolve carrying out the earlier reaction steps on precursor nitrilecompounds, and then converting the nitrile groups into tetrazolyl byreaction with an azide at or near the last step of the synthesis.

It is believed that all of the other substituents defined herein forcompounds of formula (I) may be present when compound (II) is reactedwith compound (III) in accordance with the present invention, and thesubstituents should not substantially interfere with this reaction step.It will be recognized that side reactions may occur with certainsubstituents in certain of the other reaction steps in the preferredtotal synthesis route described herein. The person skilled in the artwill recognize where side reactions could occur and avoid the sidereactions by means of suitable protecting groups, or the like.

The compounds of Formula IV as defined above form a further aspect ofthe present invention.

Preferably, the process according to the present invention furthercomprises the step of converting the compound of formula IV into acompound of formula (IVa)

where R^(4a) is C₂₋₄ alkyl or C₂₋₄ alkyl substituted by cyano, hydroxy,—CONR⁷R⁸, or an optionally protected acid group.

For example, the present invention preferably provides a process asabove for preparing a compound of formula (I), further including thestep of converting the compound of formula (IV) to the olefin

The compound of formula (IV) may be converted into the olefin via thethiocarbonate (Va)

using the Corey-Winter olefination method. For example,1,1′-thiocarbonyldiimidazole and 4-dimethylaminopyridine indichloromethane may be used to obtain the thiocarbonate, and a trivalentphosphorus reagent such as1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine is then used to convertthe thiocarbonate to the olefin. This reaction is preferably carried outin a solvent such as THF.

The olefin of Formula (V), in turn, is preferably converted to thecorresponding alcohol (VI)

by a hydroboration-oxidation sequence, such as heating withborane-tetrahydrofuran complex (BH₃—THF) in tetrahydrofuran, followed bythe addition of water, alkali metal hydroxide i and hydrogen peroxide.

Preferably, the method of the present invention then includes the stepof oxidising the above indoline alcohol compound to the correspondingindole compound of the formula

Such oxidation may conveniently be achieved by reaction withchlorotrimethylsilane and triethylamine in dichloromethane, followed bytreatment with a mild oxidizing agent, such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

Preferably, the indole alcohol of formula (VII) is then converted into acompound of formula (IVa)

This step is preferably carried out by: (i) converting the hydroxylgroup into an anionic leaving group, e.g. converting the hydroxyl groupinto trifluoromethylsulfonate by treatment with trifluoromethylsulfonicanhydride and mild base, followed by (ii) reaction with a suitablenucleophile to produce the desired group R^(4a), e.g. reaction withcyanide ion, or cyanomethylation with NCCH₂CO₂H and lithiumdiisopropylamide, or with CH₃CN and lithium diisopropylamide in aproticsolvent.

When R^(2a)—X— is a protected hydroxy group, the process according tothe invention may further comprise the step of removing the protectinggroup R^(2a) from the compound of formula (VII) and then reacting thedeprotected compound with a compound of the formulaBr—(CH₂)_(n)CR¹¹R¹²—R², wherein n, R¹¹ and R¹² are as defined above, toform a compound of the formula

The protecting group R^(2a) may conveniently be removed using aconventional O-dealkylating agent, such as boron tribromide in a solventsuch as dichloromethane.

In preferred embodiments, the present invention provides a process forpreparing a compound of formula (I), wherein Y is —CR¹⁵═CR¹⁶—,comprising the step of reacting the compound of formula (IVa) wherein Z′is an anionic leaving group, preferably Br, with a compound of theformula CHR¹⁵═CR¹⁶—R⁵ in a Heck coupling reaction to form a compound ofthe formula

The Heck coupling reaction requires the presence of a palladium salt ascatalyst, a polar solvent, a base, and a monodentate or bidentatephosphine ligand. For example, the reaction preferably usesbisdiphenylphosphinopropane, palladium dichloride in acetonitrile andtriethylamine. It has been found that, for compounds of formula VIII,the reaction can be carried out in a sealed bottle at a temperature of90° to 100° C.

When R^(2a) in formula (IX) is cyano and/or R^(4a) is cyano-C₂₋₄ alkyl,the compound of formula (IX) may be reacted with an azide, such asBu₃SnN₃, to convert the cyano groups to tetrazolyl groups.

Preferably, the compound of formula (III) is formed by epoxidation of acompound of the formula

The epoxidation is preferably a Sharpless asymmetric epoxidation, asdescribed in U.S. Pat. No. 4,471,130 or U.S. Pat. No. 4,900,847, theentire disclosure of which is incorporated herein by reference. Thisepoxidation is carried out with a titanium alkoxide, an organichydroperoxide, and a chiral glycol in an inert aprotic solvent.Preferred reagents are Ti(O^(i)Pr)₄, t-BuOOH and diethyl tartrate. Ifthe diethyl tartrate is the L-(+)-isomer, then the resulting compound offormula (III) has the structure

and the resulting compound of formula (I) has the structure

On the other hand, if the diethyl tartrate is the D-(−)-isomer, then theresulting compound of formula (III) has the structure

and the resulting compound of formula (I) has the structure

Accordingly, the present invention also provides compositions comprisinga compound of formula

substantially free of the enantiomer

as well as compositions comprising a compound of formula (Ib)substantially free of the enantiomer (Ia). The enantiomeric ratio insuch compositions is preferably at least 80:10, and more preferably atleast 90:10. In many cases, an enantiomeric ratio greater than 95:5 isobtained.

The invention is now illustrated by the following examples, whichdescribe the synthesis of the two enantiomers of formula (Ia) and (Ib)above, including the synthesis of intermediates according to the presentinvention:

Procedure I: Synthesis of 7-chloro-2-ethenylpuinoline (a)2-Bromomethyl-7-chloroquinoline

A solution of diisopropylamine (3.6 ml, 24.86 mmol) in drytetrahydrofuran (25.0 ml) at −20° C. under nitrogen was treated with a2.5 M solution of n-butyllithium in hexane (10.0 ml, 24.86 mmol). Thislithium diisopropylamide solution was stirred below −10° C. for 30 minand 7-chloroquinaldine (4.0 g, 22.6 mmol) was added in portions. Theresulting dark red solution was stirred at −10° C., increasing to 0° C.for 1 h, cooled to −30° C. and treated with chlorotrimethylsilane (4.4ml, 33.92 mol) dropwise to return a golden yellow solution. Afterstirring below −20° C. for 2 h a solution of bromine (1.2 ml, 22.6 mmol)in tetrahydrofuran (25.0 ml) was added dropwise over a 30 min periodmaintaining an addition temperature of below −20° C. at all times. Themixture was stirred below −20° C. for 1 h, quenched with water (300 ml),extracted into ethyl acetate (3×100 ml), the combined organic extractswere washed with saturated ammonium chloride solution (2×200 ml), dried(Na₂SO₄) and evaporation of the solvent afforded a brown oily solid.Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.),1:4) gave the title compound (3.62 g, 76%) as a yellow solid.Crystallised from light petroleum (b.p. 40-60° C.) as white crystals,m.p. 108-112° C. (lit. m.p. 112° C. (dec.)). v_(max) (nujol)/cm⁻¹1593.5, 1559.5. δH (270 MHz) 4.68 (2H, s, CH₂ Br); 7.50 (1H, dd, 6-H,J_(o)=8.6, J_(m)=2.0 Hz); 7.56 (1H, d, 3-H, J_(o)=8.3 Hz); 7.74 (1H, d,5-H, J_(o)=8.9 Hz); 8.06 (1H, d, 8-H, J_(m)=2.0 Hz); 8.14 (1H, d, 4-H,J_(o)=8.6 Hz). δ_(c)(67.8 MHz) 34.0 (CH₂Br), 121.4 (3-C), 125.6 (4a-C),135.9 (8a-C), 137.1 (4-C), 158.0 (2-C). Remaining signals fall in thenarrow range 128.0-128.3 ppm.

(b) (7-Chloroquinolin-2-yl)methyltriphenylphosphonium bromide

Triphenylphosphine (1.83 g, 6.99 mmol) was added portionwise to amagnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.2 g,4.69 mmol) in dry acetonitrile (10.0 ml) at 60° C. The resulting yellowsolution was heated at 60° C. for 27 h with the precipitation of a creamsolid. The cooled solution was diluted with diethyl ether (8.0 ml) andfiltered to afford the title compound as a cream solid (1.95 g, 80%).Crystallised from ethanol and ethyl acetate as a cream microcrystallinesolid, m.p. >200° C.; (Found: C, 64.61; H, 4.22; N, 2.62; Cl, 6.82.C₂₈H₂₂ClBrNP requires C, 64.82; H, 4.27; N, 2.70, Cl, 6.83%). ν_(max)(nujol)/cm⁻¹ 1610.0, 1594.0. δH (270 MHz) 5.94 (2H, d, CH₂ P, ³J=14.2Hz); 7.43 (1H, dd, 6-H, J_(o)=8.6, J_(m)=2.0 Hz); 7.50 (1H, d, 8-H,J_(m)=2.0 Hz); 7.57-7.95 (16H, m, ArH); 8.03 (1H, d, 3-H, J_(o)=8.6 Hz);8.11 (1H, d, 4-H, J_(o)=8.6 Hz); m/z 437.4 (1.18), 262.3 (11.01), 177.1(3.13), 43.1 (100).

(c) Diethyl 7-chloro-2-quinolylmethylphosphonate

Method 1

A magnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.0g, 3.91 mmol) and triethyl phosphite (0.74 g, 4.45 mmol) in dry toluene(10.0 ml) was heated under reflux for 24 h. The cooled solution wasadsorbed onto a quantity of silica (ca. 5.0 g) and column chromatography(ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) provided unreacted2-bromomethylquinoline (0.12 g, 0.469 mmol-12%) as brown crystals.Further elution (ethyl acetate) secured the title compound (0.88 g, 72%)as a yellow/brown oil. Distilled at 240° C. at 0.05 mmHg using aKugelrohr short-path distillation apparatus as a bright yellow oil whichcrystallised on standing (m.p. 33-37° C.); (Found: C, 53.17; H, 5.40; N;4.31; Cl, 11.22. C₁₄H₇ClNO₃P requires C, 53.6; H, 5.46; N, 4.46; Cl,11.3%); ν^(max) (thin film)/cm⁻¹ 3060.5, 2981.5, 1612.5, 1598.5, 1559.5.δ_(H) (270 MHz) 1.27 (6H, t, 2×CH ₂CH₃ , ³J=6.9 Hz); 3.60 (2H, d, CH₂ P,²J=22.4 Hz); 4.11 (4H, m, 2×CH₂ CH ₃); 7.47 (1H, dd, 3-H, J_(o)=7.0,⁴J_(3H.P)=0.8 Hz); 7.51 (1H, dd, 6-H, J_(o)=8.4, J_(m)=1.5 Hz); 7.72(1H, d, 5-H, J_(o)=8.9 Hz); 8.05 (1H, d, 8-H, J_(m)=1.7 Hz); 8.06 (1H,d, 4-H, J_(o)=8.3 Hz). δ_(c) (67.8 MHz) 16.15 (CH ₂CH₃, d, ³J_(C.P)=6.1Hz); 37.0 (CH₂P, d, ¹J_(C.P)=134.3 Hz); 62.3 (CH₂CH₃, d, ²J_(C.P)=6.1Hz); 122.3 (3-C, d, ³J_(C.P)=2.5 Hz), 125.1 (4a-C), 135.3 (7-C), 136.2(4-C); 147.9 (8a-C), 154.3 (2-C, d, ²J_(C.P)=8.6 Hz). Remaining 315.3,313.2 (7.52, 22.18, M⁺), 277.3 (2.21), 242.1, 240.1 (1.79, 5.13), 193.1(6.84), 179.1, 177.1 (33.1, 100), 142.2 (3.65), 109.1 (4.57).

Method 2

A 2.5 M solution of n-butyllithium in hexane (25.0 ml, 62.15 mmol) wasadded dropwise to a magnetically stirred solution of diisopropylamine(9.0 ml, 62.15 mmol) in tetrahydrofuran (80.0 ml) at −20° C. undernitrogen. The resulting pale yellow solution was stirred below −10° C.for 30 min and treated with 7-chloroquinaldine (10.0 g, 56.5 mmol) inportions. The solution of the dark red anion was stirred below −5° C.for 1 h then cooled to −20° C. and treated dropwise with a solution ofdiethyl chlorophosphate (9.0 ml, 62.3 mmol) in tetrahydrofuran (20.0ml). Stirred below 0° C. for 1h, recooled to −20° C. and treateddropwise with a further quantity of lithium diisopropylamide (62.15mmol). This dark grey mixture was allowed to warm to 0° C. over 20 minthen quenched with water (500 ml), extracted into ethyl acetate (3×200ml), the combined organic extracts were washed with brine (2×200 ml),dried (Na₂SO₄) and evaporated to provide an orange/brown oil. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 7:3)provided the title compound as an orange solid (12.6 g, 71%) whosephysical and spectroscopic properties were identical to those describedabove.

(d) 7-Chloro-2-ethenylquinoline

A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) intetrahydrofuran (15.0 ml) at −10° C. under nitrogen was treated dropwisewith a 2.5 M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol).After stirring below 0° C. for 30 min the pale yellow solution wascooled to −20° C. and a solution of diethyl7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) intetrahydrofuran was added dropwise. The resulting dark green solutionwas stirred below 0° C. for 1 h, cooled to −10° C. and treated withparaformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15min after which the cooling bath was removed and the mixture was stirredat 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethylacetate (3×100 ml), the combined organic extracts were washed with brine(3×200 ml), dried (Na₂SO₄) and the solvent was removed in vacuo to givea dark brown solid. Column chromatography (ethyl acetate-light petroleum(b.p. 40-60° C.), 1:19) provided the title compound (1.80 g, 59%) aspale yellow crystals. Crystallised from ethyl acetate and lightpetroleum (b.p. 40-60° C.) as cream crystals, m.p. 79.7-80° C. (Found:C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C₁₁H₈ClN requires C, 69.67; H,4.25; N, 7.39; Cl, 18.69%); ν_(max) (nujol)/cm⁻¹ 1628, 1609; δ_(H) (270MHz) 5.67 (1H, dd, 2′-H, ³J_(2′,1′)=10.89, ²J_(2′,2″)=1.0 Hz); 6.29 (1H,dd, 2″-H, ³J_(2″,1′)=17.7, ²J_(2″,2′)=0.8 Hz); 7.02 (1H, dd, 1′-H,³J_(1′,2″)=17.5, ³J_(1′,2′)=10.9 Hz); 7.42 (1H, dd, 7-H, J_(o)=8.8,J_(m)=2.1 Hz); 7.53 (1H, d, 3-H, J_(o)=8.9 Hz); 7.66 (1H, d, 5-H,J_(o)=8.9 Hz); 8.03 (1H, d, 4-H, J_(o)=8.3 Hz); 8.05 (1H, s, 8-H). δ_(c)(67.8 MHz) 118.6 (2′-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0(4-C); 137.5 (1′-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fallin the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M⁺), 165.0,163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).

Procedure 2: Synthesis of 7-Benzyloxyindoline (a) 7-Benzyloxyindoline

A magnetically stirred solution of 7-benzyloxyindole (16.0 g, 71.66mmol) in glacial acetic acid (200 ml) at 10° C. under nitrogen wastreated with sodium cyanoborohydride (10.0 g, 0.159 mol) in portions viaa powder funnel maintaining an addition temperature of below 17° C.Resulting white suspension was stirred below 20° C. for 4 h and quenchedwith water (300 ml). Evaporation in vacuo gave a colourless oil whichwas diluted with ethyl acetate (300 ml) treated with 2M sodium hydroxide(400 ml) and stirred vigorously for 16 h. The organic layer wasseparated, the aqueous was extracted with ethyl acetate (3×100 ml), thecombined organic phases were washed with aqueous 2M NaOH_((aq)) (200 ml)brine (2×200 ml), dried (Na₂SO₄) and evaporation of the solvent gave thecrude product as an oily white solid. Column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 1:9) provided the titlecompound (14.1 g, 89%) as white crystals. Crystallised from ethylacetate and light petroleum (b.p. 40-60° C.) as colourless plates (m.p.58-60° C.). (Found: C, 80.04; H, 6.58; N; 6.19. C₁₅H₁₅NO requires C,79.97; H, 6.71; N, 6.22%); ν_(max) (nujol)/cm⁻¹ 3332, 30338, 1885, 1618,1591; δ_(H) (270 MHz) 3.02 (2H, 2×2-H, ³J_(2,3)=8.4 Hz); 3.51 (2H,2×3-H, ³J_(3.2)=8.6 Hz); 3.80 (1H, bs, N-H); 5.02 (2H, s, CH₂ Ph); 6.65(2H, m, 4-H, 5-H); 6.80 (1H, m, 6-H); 7.33 (5H, m, Ph). δ_(c) (67.8 MHz)30.3 (2-C); 47.62 (3-C); 70.1 (OCH₂Ph); 110.8 (6-C); 117.5 (5-C); 118.9(4-C); 130.4 (3a-C); 137.2 (7a-C); 140.9 (benzyl ipso-C); 144.4 (7-C).Remaining signals lie between 127.3-128.4 ppm; m/z 225.2 (17.24, M⁺),134.1 (100), 116.1 (14.06), 91.1 (29.15).

Procedure 3: Synthesis of (2R/S-trans)-3-(3-bromophenyl)-Oxiranemethanol(a) Trans-3-(3-bromophenyl)-2-propenoic acid

A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treatedwith piperidine (4.0 ml, 40.45 mmol) and heated at ˜90° C. for 90 minthen under reflux for 30 min. The cooled mixture was poured onto ice(200 g) and water (300 ml) then acidified to pH=1 with conc.hydrochloric acid. Filtration afforded a white solid which was washedwith water (4×200 ml), dried by suction and placed in an oven at 70° C.for 48 h until constant weight was obtained (96.02 g, 90%); ν_(max)(nujol)/cm⁻¹ 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δ_(H) (270 MHz)6.45 (1H, d, 2-H, ³J_(2,3)=16.2 Hz); 7.28 (1H, t, 5′-H, J_(o)=7.8 Hz);7.48 (1-H, dt, 4′-H, J_(o)=7.9, J_(m)=1.3 Hz); 7.54 (1-H, dt, 6′-H,J_(o)=7.9, J_(m)=1.0 Hz); 7.70 (1-H, t, 2′-H, J_(m)=1.8 Hz); 7.71 (1H,d, 3-H, ³J_(3,2)=15.8 Hz).

(b) Methyl trans 3-(3-bromophenyl)-2-propenoate (first method)

A solution of trans-3-(3-bromophenyl)-2-propenoic acid (0.405 mol) inmethanol (300 ml) was treated with conc. sulfuric acid (6.0 ml) andheated under reflux for 10 h. The cooled mixture was filtered to affordthe title compound (46.14 g, 47%) as brilliant white crystals, m.p.53-55° C. (Found: C, 50.10; H, 3.58; Br; 33.21. C₁₀H₉BrO₂ requires C,49.82; H, 3.76; Br, 33.14%); ν_(max) (nujol)/cm⁻¹ 1730.5, 1715.0, 1644;δ_(H) (270 MHz) 3.81 (3H, s, OCH₃ ); 6.43 (1H, d, 2-H, ³J_(2,3)=16.2Hz); 7.25 (1H, t, 5′-H, J_(o)=7.8 Hz); 7.43 (1H, dt, 4′-H, J_(o)=7.9,J_(m)=1.0 Hz); 7.50 (1H, dt, 6′-H, J_(o)=7.9, J_(m)=1.0 Hz); 7.60 (1H,d, 3-H, ³J_(3,2)=16.2 Hz); 7.66 (1H, t, 2′-H, J_(m)=1.7 Hz). δ_(c) (67.8MHz) 51.8 (OCH₃); 123.0 (3′-C); 133.0 (4′-C); 136.4 (1′-C); 143.1 (3-C);166.9 (CO₂Me). Remaining signals lie in the range 119.3-130.7 ppm; m/z242.0, 240.0 (46.67, 47.64, M⁺), 211.0, 209.0 (72.69, 74.00), 182.9,180.9 (15.67, 16.83), 161.0 (4.19), 130.0 (9.44), 102.1 (100).

The filtrate was evaporated in vacuo to give a brown solid which wasdissolved in ethyl acetate (400 ml), washed with 10% aqueous sodiumbicarbonate (2×300 ml), dried (Na₂SO₄) and evaporation of the solventprovided the title product as off-white crystals (48.80 g, 50%).

(c) Ethyl trans-3-(3-bromophenyl)-2-propenoate

A magnetically stirred solution of triethyl phosphonoacetate (12.12 g,54.0 mmol) in dry tetrahydrofuran (30.0 ml) at −10° C. under an N₂atmosphere was treated portionwise with a 60% dispersion of sodiumhydride in mineral oil (2.16 g, 54.0 mmol). Resulting solution wasstirred below 10° C. for 1 h, cooled to −5° C. and treated with asolution of 3-bromobenzaldehyde (10.0 g, 54.0 mmol) in THF (20.0 ml)dropwise. The reaction mixture was stirred below 25° C. for 3 h,quenched with water (300 ml), extracted into ethyl acetate (3×100 ml),the combined organic extracts were washed with brine (2×100 ml), dried(Na₂SO₄) and the solvent was removed in vacuo to reveal a pale yellowoil. Dissolution in light petroleum (b.p. 30-40° C.) (50.0 ml) andcooling to −30° C. afforded the title compound (11.94 g, 87%) as a whitecrystalline solid, m.p. 26-28° C.; (Found C, 52.03; H, 4.20; Br, 31.38.C₁₁H₁₁BrO₂ requires C, 51.79; H, 4.35; Br, 31.32%); ν_(max) (thinfilm)/cm⁻¹ 3062.0, 2981.0, 1717.0, 1640.0, 1592; δ_(H) (270 MHz) 1.34(3H, t, CH₂CH₃ , ³J=7.1 Hz); 4.27 (2H, q, CH₂ CH₃, ³J=7.3 Hz); 6.43 (1H,d, 2-H, ³J_(2,3)=15.8 Hz); 7.25 (1H, t, 5′-H, J_(o)=7.9 Hz); 7.43 (1H,dd, 4′-H, J_(o)=7.6, J_(m)=1.0 Hz); 7.50 (1H, dt, 6′-H, J_(o)=7.9,J_(m)=1.0 Hz); 7.60 (1H, d, 3-H, ³J_(2,3)=16.2 Hz); 7.66 (1H, t, 2′-H,J=1.8 Hz). δ_(C) (67.8 MHz) 14.3 (OCH₂ H ₃); 66.7 (OCH₂CH₃); 123.0(3′-C); 133.0 (4′-C); 136.6 (1′-C) 142.8 (3-C); 166.5 (CO₂Me). Remainingsignals lie in the range 119.7-130.7 ppm; m/z 256.9, 254.9 (2.46, 3.99,M⁺), 255.9, 254.0 (21.6, 22.26), 227.9, 226.0 (9.49, 9.51), 210.9, 208.9(46.92, 47.72), 184.9, 182.9 (95.49, 100), 156.9, 154.9 (51.38, 52.63),102.0 (56.89).

(d) Methyl trans-3-(3-bromophenyl)-2-propenoate (second method)

Prepared in accordance with the above procedure using methyl diethylphosphonoacetate to afford the title compound as white crystals (57%).Physical and spectroscopic data for this compound were as describedabove.

(e) Trans-3-(3-bromophenyl)-2-propenol

A vigorously stirred solution of ethyltrans-3-(3-bromophenyl)-2-propenoate (26.71 g, 0.105 mol) in dry toluene(150 ml) at −5° C. (ice-EtOH) under nitrogen was treated with lithiumaluminium hydride (3.98 g, 0.105 mol) in one portion. The reactiontemperature was allowed to gradually warm to room temperature over 30min., at 25° C. the reaction became quite exothermic (25-40° C.) withthe formation of a grey gelatinous precipitate. Stirring was continuedfor 1 h, after which the reaction was carefully quenched with water (300ml) and ice (200 g) then allowed to stand at 25° C. for 30 min. Themixture was filtered through Celite (Registered Trade Mark) and theresidue was washed with ethyl acetate (2×200 ml). The filtrate wasextracted with the organic washings, the combined organic phases werewashed with brine (3×300 ml), water (300 ml), dried (Na₂SO₄) andevaporated to give the title compound as a pale yellow oil (21.42 g,96%). Distillation at 120° C. at 0.05 mmHg. gave a colourless oil.(Found C, 50.73; H, 4.12; Br, 37.53. C₉H₉BrO requires C, 50.73; H, 4.26;Br, 37.50%); ν_(max) (thin film)/cm⁻¹ 3325.5 (br. OH), 2862.0, 1653.0,1591.0, 1562.5; δ_(H) (270 MHz) 2.15 (1H, bs, 1-OH), 4.30 (2H, dd,2×1-H, ³J_(1,2)=5.5, ⁴J_(1,3)=1.5 Hz), 6.33 (1H, dt, 2-H, ³J_(2,3)=15.8,³J_(2,1)=5.3 Hz), 6.53 (1H, dt, 3-H, ³J_(3,2)=16.2, ⁴J_(3,1)=1.3 Hz),7.15 (1H, t, 5′-H, J_(o)=7.8 Hz), 7.26 (1H, dt, 6′-H, J_(o)=7.6,J_(m)=1.3 Hz), 7.35 (1H, dt, 4′-H, J_(o)=7.9, J_(m)=1.6 Hz), 7.50 (1H,t, 2′-H, J_(m)=1.6 Hz). δ_(C) (67.8 MHz) 63.2 (1-C), 122.7 (3′-C), 125.0(2-C), 129.2 (5′-H), 138.8 (1′-C). The remaining signals fall in thenarrow range 130.0 to 130.4 ppm; m/z 214.1, 212.1 (44.86,49.78, M⁺),196.0, 194.0 (1.47, 1.03), 185.0, 183.0 (10.81, 12.19), 172.0, 170.0(46.47, 49.07), 158.0, 156.0 (15.47, 15.80), 133.1, 131.1 (36.29,25.66), 104.1 (100).

(f) (2S-Trans)-3-(3-bromophenyl)oxiranemethanol

A magnetically stirred solution of L-(+)-diethyl tartrate (2.69 g, 13.11mmol) in dry dichloromethane (60.0 ml) at −30° C. under nitrogen wastreated sequentially with powdered 4 Å molecular sieves (10.93 g),titanium(IV) isopropoxide (2.65 ml, 8.74 mmol) and a 3.0 M solution oftert-butyl hydroperoxide in isooctane (74.4 ml, 0.223 mol). Theresulting white suspension was stirred below −10° C. for 2 h. thentreated dropwise with a solution of trans-3-(3-bromophenyl)-2-propenol(23.24 g, 0.109 mol) in dichloromethane (30.0 ml) at −30° C. Stirredbetween −10° C. and −30° C. for 6 h treated with a solution of 10% NaOHin saturated brine (135 ml), stirring was continued below 10° C. for 30min. after which a mixture of MgSO₄ (29.75 g, 0.248 mol) and celite(20.31 g) was added. After stirring at room temperature for 1 h. themixture was filtered through Celite and the residue was washed withdichloromethane (3×100 ml). The combined organic filtrates were washedwith brine (3×300 ml), dried (Na₂SO₄) and evaporated to give a yellowoil (27.78 g). Column chromatography (ethyl acetate-light petroleum(b.p. 40-60° C.), 3:7) provided the title compound (17.24 g, 70%) as apale yellow oil. Distilled at 160-185° C. at 0.1 mm′g. using a Kugelrohrshort path distillation apparatus as a colourless oil. (Found C, 47.36;H, 4.01; Br, 34.31. C₉H₉BrO₂ requires C, 47.19; H, 3.96; Br, 34.88%);[α]_(D) ²⁵ −38.9 (c=0.017 gml⁻¹, CHCl₃); ν_(max) (nujol)/cm⁻¹ 3401.5(br. OH), 2926.5, 1598.5, 1571.0; δ_(H) (270 MHz) 2.20 (1H, bq, OH,³J_(OH,1-H)=7.4, ³J_(OH,1′-H)=5.4 Hz); 3.18 (1H, m, 2-H); 3.80 (1H, dq,1-H, ²J_(1,1′)=12.9, ³J_(1,OH)=7.4, ³J_(1,2)=3.8 Hz); 3.91 (1H, d, 3-H,³J_(3,2)=2.3 Hz); 4.04 (1H, dq, 1′-H, ²J_(1′,1)=12.9, ³J_(1′,OH)=5.0,³J₁′,2=2.3 Hz); 7.22 (2H, m, 5′-H, 6′-H); 7.43 (2H, m, 2′-H, 4′-H).δ_(C) (67.8 MHz) 50.4 (2-C); 56.65 (1-C); 58.3 (3-C); 118.4 (3′-C);120.1 (6′-C); 134.8 (1′-C). The remaining signals lie in the range124.3-127.1 ppm; m/z 229.9, 227.9 (8.09, 8.87, M⁺), 215.9, 213.9 (12.78,14.91), 185.9, 183.9 (14.24, 182.9), 104.0 (44.32), 89.1 (100).

(g) (2R)-(+)-Trans-3-(3-bromophenyl)oxiranemethanol

The title compound was prepared from trans-3-(3-bromophenyl)-2-propenolby a sequence analogous to that described above for compound (9a) butusing D-(−)-diethyl tartrate. Column chromatography (ethyl acetate-lightpetroleum (b.p. 40-60° C.), 3:7) provided the title compound (73%) as apale yellow oil. Distilled at 160-185° C. at 0.1 mmHg. using a Kugelrohrshort path distillation apparatus as a colourless oil; [a]_(D) ²⁵ +37.6(c=0.020 gml⁻¹, CHCl₃).

(h) Preparation of racemic trans-3-(3-bromophenyl)oxiranemethanol

A magnetically stirred solution of m-chloroperbenzoic acid (3.57 g,10.33 mmol) in dichloromethane (60.0 ml) at 25° C. was treated dropwisewith a solution of trans-3-(3-bromophenyl)-2-propenol (2.0 g, 9.39 mmol)in dichloromethane (20.0 ml). After stirring. for 16 h the mixture wasdiluted with dichloromethane (200 ml), washed with aqueous 1M NaOH(2×200 ml), brine (2×200 ml) and dried (Na₂SO₄). Evaporation of thesolvent in vacuo returned the crude epoxide as a pale yellow oil (2.06g). Column chromatography (ethyl acetate-light petroleum (b.p. 40-60°C.), 3:7) provided the title compound (1.53 g, 71%) as a pale yellowoil.

EXAMPLE 1 Synthesis of(2S,3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)yroyane-1,2-diol

Magnesium perchlorate (16.63 g, 74.52 mmol) was added in portions to amagnetically stirred solution of(2S-trans)-3-(3-bromophenyl)oxiranemethanol (16.32 g, 71.26 mmol) in dryacetonitrile (100 ml) at 5° C. under nitrogen. After stirring for 10min. all of the magnesium salts had dissolved and the resulting intenseyellow solution was treated with 7-benzyloxyindoline (16.77 g, 74.52mmol) in acetbnitrile (30.0 ml) dropwise at 0° C. (ice-H₂O). The darkbrown solution was stirred at 25° C. for 20 h, quenched with saturatedaqueous NaHCO₃ (300 ml), extracted with ethyl acetate (3×200 ml), thecombined organic phases were washed with brine (3×200 ml), dried(Na₂SO₄) and the solvent removed in vacuo to provide a yellow/brown gum.Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.),3:7) provided the title compound (27.37 g, 87%) as a grey/green oilwhich crystallised on standing. Recrystallised from diethyl ether at−20° C. as white crystals, m.p. 61-66° C. (Found: C, 63.51; H, 5.78; N,2.84. C₂₄H₂₄BrNO₃ requires C, 63.44; H, 5.32; N, 3.08%); [α]_(D) ²⁵−311.1 (c=0.009 gml⁻¹, CHCl₃); ν_(max) (nujol)/cm⁻¹ 3353.0 (br. OH),1584.0, 1565.0; δ_(H) (270 MHz) 2.27 (1H, bs, OH); 2.66 (3H, m, OH,2×indoline 2-H); 3.10 (1H, m, indoline 3-H); 3.30 (1H, m, indoline 3-H);3.85 (2H, dq, 2×1-H, ²J_(1,1)=11.5, ³J_(1,2)=4.0 Hz); 4.22 (1H, m, 2-H);5.16 (2H, s, CH₂ Ph); 5.38 (1H, d, 3-H, ³J_(3,2)=10.2 Hz); 6.65-7.49(12H, m, 12 ArH). δ_(C) (67.8 MHz) 29.2 (indoline 2-C); 46.5 (indoline3-C); 61.7 (3-C); 64.8 (1-C); 69.9 (C-2); 70.9 (CH₂Ph); 112.2 (indoline6-C); 118.1 (indoline 5-C); 120.3 (indoline 4-C); 122.4 (3′-C); 136.4(1′-C); 138.5 (indoline 7a-C); 139.5 (benzyl ipso-C); 145.0 (indoline7-C). The remaining signals lie between 127.5-136.4 ppm and could not beassigned with any certainty; m/z 455.3, 453.3 (0.58, 0.74, M⁺), 394.2,392.2 (7.81, 7.90), 304.1, 302.1 (4.80, 9.32), 225.2 (8.35), 171.0,169.0 (5.29, 5.79), 134.1 (34.82), 118.1 (1.35), 59.1 (100).

EXAMPLE 2 Synthesis of(2R,39)-(+)-3-(3-bromorhenyl)-3-(7-benzyloxyindolin-1-yl)proyane-1,2-diol

The title compound was prepared from(2R-trans)-3-(3-bromophenyl)oxiranemethanol by a sequence analogous tothat described above in Example 1. Column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 3:7) provided the titlecompound (77%) as a grey/brown foam. Recrystallised from diethyl etherat -20° C. as brown/grey prisms, m.p. 59-60° C; [α]_(D) ²⁵ +312.9(c=0.009 gml⁻¹, CHCl₃).

EXAMPLE 3 Synthesis of(1R/S)-(+/−)-7-chloro-2-(2-(3-[1-(7-(1H-tetrazol-5-ylmethoxy)indol-1-yl)-4-(1H-tetrazol-5-yl)butyl]phenyl)ethenyl)quinoline(a)(2S,3R)-(−)-7-Benzyloxy-1-[1-(3-bromophenyl)-1-(1,3-dioxolane-2-thione-4-yl)methyl]indoline

A solution of(2S,3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propane-1,2-diol(11.42 g, 25.72 mmol), 1,1′-thiocarbonyldiimidazole (6.50 g, 36.47 mmol)and 4-dimethylaminopyridine (0.10 g, 0.82 mmol) in dry dichloromethane(120 ml) was stirred at 25° C. under nitrogen for 4 h and adsorbed ontosilica (ca. 25.0 g). Column chromatography (ethyl acetate-lightpetroleum (b.p. 40-60° C.), 1:4) provided the title compound (11.66 g,91%) as a pale yellow oil which crystallised on standing to afford anorange/brown foam. (Found: C, 60.82; H, 4.31; N, 2.61; Br, 16.21; S,6.28. C₂₅H₂₂BrNO₃S requires C, 60.49; H, 4.47; N, 2.82; Br, 16.10; S,6.46%); [α]_(D) ²⁵ −198° (c=0.007 gml⁻¹, CHCl₃); ν_(max) (nujol)/cm⁻¹1591; δ_(H) (270 MHz) 2.70 (2H, m, 2×indoline 2-H); 3.05 (1H, m,indoline 3-H); 3.25 (1H, m, indoline 3-H); 4.76 (2H, m, dioxolane2×4-H); 5.17 (2H, q, CH₂ Ph, ²J=11.1 Hz); 5.37 (1H, m, dioxolane 5-H);5.72 (1H, d, 1-H, ³J_(1,dioxoiane 4-H)=10.2 Hz); 6.80 (3H, m, indoline4-H, 5-H, 6-H); 7.06-7.48 (10H, m, 10ArH). δ_(C) (67.8 MHz) 29.2 (2-C);47.0 (3-C); 61.5 (1′-C); 70.89 (CH₂ Ph); 73.0 (dioxolane 5-C); 79.6(dioxolane 4-C); 111.9 (6-C); 118.0 (5-C); 121.2 (4-C); 122.7 (3′-C);136.0 (benzyl ipso-C); 145.4 (7-C); 191.5 (dioxolane 2-C). The remainingsignals lie between 126.8-131.1 ppm; m/z 497.2, 495.2 (3.60, 3.82, M⁺),394.3, 392.3 (8.34, 8.38), 330.2, 328.1 (6.08, 7.09), 225.1 (14.70),134.0 (75.04), 118.1 (5.81), 91.1 (100).

(b)(2R,3S)-(+)-7-Benzyloxy-1-[1-(3-bromophenyl)-1-(1,3-dioxolane-2-thione-4-yl)methyl]indoline

The title compound was prepared from(2R,3S)-(+)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propane-1,2-diolby a sequence analogous to that described immediately above. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)provided the title compound (87%) as a yellow foam; [α]_(D) ¹⁷ +217(c=0.011 gml⁻¹, CHCl₃).

(c) (1R)-(−)-7-Benzyloxy-1-[1-(3-bromophenyl)prop-2-enyl]indoline

A magnetically stirred solution of(2S,3R)-(−)-7-benzyloxy-1-[1-(3-bromophenyl)-1-(1,3-dioxolane-2-thione-4-yl)methyl]indoline(11.60 g, 23.39 mmol) in dry tetrahydrofuran (80.0 ml) under nitrogenwas treated with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (10.8ml, 58.47 mmol) in one portion. The mixture was degassed and flushedwith nitrogen (×3) then heated at 50-60° C. for 7 h. The cooled solutionwas adsorbed onto silica (ca. 30.0 g) and column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 1:9) gave the title compoundas a golden yellow oil (8.50 g, 87%). (Found C, 68.65; H, 5.10; N, 3.25;Br, 18.90. C₂₄H₂₂BrNO requires C, 68.58; H, 5.28; N, 3.33; Br, 19.01%);[α]_(D) ²⁵ −93° (c=0.012 gml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 3063.5,3031.5, 2939.0, 1591.0, 1566.5, 1483.5; 5, δ_(H) (270 MHz) 2.90 (2H, m,2×indoline 2-H); 3.23 (1H, m, indoline 3-H); 3.39 (1H, m, indoline 3-H);5.04 (2H, q, CH₂ Ph, ²J=11.6 Hz); 5.08-5.34 (2H, m, 2×3-H); 6.11 (2H, m,1-H, 2-H); 6.70 (3H, m, indoline 4-H, 5-H, 6-H); 7.14 (1H, t, 5′-H,J_(o)=7.9 Hz); 7.22-7.39 (7H, ArH); 7.50 (1H, t, 2′-H, J_(m)=1.5 Hz).δ_(C) (67.8 MHz) 29.2 (2-C); 47.5 (3-C); 62.2 (1′-C); 70.9 (CH₂ Ph);112.9 (6-C); 118.1 (5-C); 118.9 (3-C*); 119.5 (4-C*); 122.4 (3′-C);135.0 (benzyl ipso-C); 143.6 (7a-C); 145.1 (7-C). The remaining signalslie between 126.6-129.8 ppm and could not be assigned with anycertainty; m/z 421.3, 419.3 (11.95, 13.72), 330.2, 328.1 (34.60, 37.43),224.2 (20.33), 197.0, 195.0 (13.59, 14.40), 134.1 (37.57), 116.1 (100).

*These signals may be interchangeable.

(d) (1S)-(+)-7-Benzyloxy-1-[1-(3-bromophenyl)prop-2-enyl]indoline

The title compound was prepared from(3S,2R)-(+)-7-benzyloxy-1-[1-(3-bromophenyl)-1-(1,3-dioxolane-2-thione-4-yl)methyl]indolineby a sequence analogous to that described immediately above. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:9)provided the title compound (83%) as a pale yellow oil; [α]_(D) ¹⁷ +97(c=0.010 gml⁻¹, CHCl₃).

(e) (3R)-(−)-3-(3-Bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol

A 1.0 M solution of borane-tetrahydrofuran complex (BH₃-THF) intetrahydrofuran (38.1 ml, 38.10 mmol) was added dropwise to amagnetically stirred solution of(1R)-(−)-7-benzyloxy-1-[1-(3-bromophenyl)prop-2-enyl]indoline (16.0 g,38.1 mmol) in dry tetrahydrofuran (200 ml) under nitrogen at 0° C. Thereaction mixture was heated under reflux for 8.5 h, during which timetwo further aliquots of 1.0 M BH₃-THF in tetrahydrofuran were added(1×15.0 ml and 1×5.0 ml) until TLC inspection indicated that no furtherstarting olefin remained. The reaction mixture was cooled to 0° C.,sequentially treated with water (21.0 ml), 3M sodium hydroxide solution(21 ml) and 30% hydrogen peroxide (21.0 ml) then stirred at roomtemperature for 16 h. Quenched with brine (400 ml), extracted with ethylacetate (3×200 ml), the combined organic phases were washed with brine(200 ml), dried (Na₂SO₄) and evaporated to yield a brown oil. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)gave the title compound as a pink oil (11.70 g, 70%). [α]_(D) ²⁵ −280°(c=0.011 gml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 3391 (br. OH), 3063,3031, 2939, 1591; δ_(H) (270 MHz) 1.89 (1H, m, 1×2-H); 2.26 (1H, m,1×2-H); 2.69 (2H, m, indoline 2×2-H); 3.13 (1H, m, indoline 1×3-H); 3.30(1H, bs, 1-OH); 3.43 (1H, m, indoline 1×3-H); 3.81 (2H, m, 2×1-H); 5.17(2H, s, CH₂ Ph); 5.59 (1H, dd, 3-H, ³J_(3,2)=11.2 Hz, ³J_(3,2′)=4.0 Hz);6.77 (3H, m, indoline 4-H, 5-H, 6-H); 7.06 (2H, m, 5′-H,6′-H); 7.31-7.51(7H, ArH). δ_(C) (67.8 MHz) 29.1 (2-C); 32.7 (indoline 2-C); 45.6(indoline 3-C); 58.2 (1-C); 61.7 (3-C); 70.9 (CH₂Ph); 112.2 (indoline6-C); 118.1 (indoline 5-C); 120.6 (indoline 4-C); 122.3 (3′-C); 133.4(indoline 3a-C); 136.7 (1′-C); 139.0 (benzyl ipso-C); 142.4 (indoline7a-C); 145.7 (indoline 7-C). The remaining signals lie between126.5-130.7 ppm and cannot be assigned with any certainty; m/z 439.1,437.1 (2.69, 3.32, M⁺), 394.2, 392.2 (1.06, 1.09), 348.1, 346.1 (5.33,5.60), 225.1 (18.26), 172.0, 170.0 (33.75, 34.31), 134.0 (100), 118.0(2.79), 91.1 (67.26).

(f) (3S)-(+)-3-(3-Bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol

The title compound was prepared from(1S)-(+)-7-benzyloxy-1-[1-(3-bromophenyl)]prop-2-enylindoline by asequence analogous to that described immediately above. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)provided the title compound (70%) as a pink oil; [α]_(D) ¹⁷ +280(c=0.010 gml⁻¹, CHCl₃).

(g) (3R)-(−)-3-(3-Bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ol

A stirred solution of(3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.0g, 2.28 mmol) in dry dichloromethane (30.0 ml) under nitrogen at 5° C.was treated with triethylamine (0.52 ml, 3.77 mmol) followed bychlorotrimethylsilane (0.32 ml, 2.52 mmol) dropwise. The resultingsuspension was stirred at room temperature for 20 min, treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.52 mmol) andstirred at room temperature until the reaction was judged to be completefrom TLC inspection (˜30 min). The solvent was removed by evaporation,the residue was taken up in ethyl acetate (200 ml), washed with 2Maqueous sodium hydroxide (3×100 ml), brine (100 ml) and 2M aqueoushydrochloric acid (2×100 ml). Evaporation of the dried organic extracts(Na₂SO₄) gave a yellow/brown oil. Column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compoundas a yellow oil (0.80 g, 80%). [α]_(D) ²⁶ −157 (c=0.014 gml⁻¹, CHCl₃);ν_(max) (thin film)/cm⁻¹ 3418.5 (br. OH), 3064.5, 3033.5, 2935.5,2879.0, 1593.5, 1570.5; δ_(H) (270 MHz) 2.35 (2H, m, 2×2-H); 3.50 (2H,m, 2×1-H); 5.13 (2H, q, CH₂Ph, ²J=11.1 Hz); 6.6 (m, 2H, 3-H, indole3-H); 6.72 (1H, dd, indole 6-H, J_(o)=7.6 Hz, J_(m)=0.7 Hz); 6.90 (1H,dd, indole 4-H, J_(o)=8.3 Hz, J_(m)=0.8 Hz); 7.00 (2H, m, indole 5-H,5′-H); 7.15 (1H, d, indole 2-H, ³J_(2,3)=3.0 Hz); 7.19-7.40 (8H, m,8ArH). δ_(C) (67.8 MHz) 38.4 (2-C); 56.4 (3-C); 59.3 (1-C); 70.7(PhCH₂); 103.2 (indole 3-C); 104.3 (indole 6-C); 114.3 (indole 4-C);120.1 (indole 5-C); 122.5 (3′-C); 125.0 (indole 2-C); 131.8 (1′-C);136.4 (benzyl ipso-C); 144.9 (indole 7a-C); 146.5(indole 7-C). Theremaining signals lie between 126.5-130.7 ppm and cannot be assignedwith any certainty.

(h) (3S)-(+)-3-(3-Bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ol

The title compound was prepared from(3S)-(+)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (13b)by a sequence analogous to that described immediately above. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)provided the title compound (74%) as a yellow/brown oil; [α]_(D) ²² +188(c=0.007 gml⁻¹, CHCl₃).

(i) (1R)-(−)-7-Benzyloxy-1-[1-(3-bromophenyl)-4-cyanobutyl]indole

Acetonitrile (2.72 ml, 52.19 mmol) in dry tetrahydrofuran (5.0 ml) wasadded dropwise to a magnetically stirred solution of 2.5 Mn-butyllithium in hexane (22.0 ml, 54.80 mmol) in tetrahydrofuran (100ml) at −75° C. under nitrogen. The resulting white suspension wasstirred below −70° C. for 1 h to ensure complete formation of the lithioacetonitrile reagent.

A solution of(3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ol (5.10 g,11.62 mmol) and 2,6-lutidine (1.24 g, 11.62 mmol) in dry dichloromethane(20.0 ml) was added dropwise to a magnetically stirred solution oftrifluoromethanesulfonic anhydride (2.20 ml, 13.10 mmol) indichloromethane (40.0 ml) at −10° C. under nitrogen over a 25 min.period. The resulting grey solution was stirred below −10° C. for 20min., quenched with water (250 ml), extracted into dichloromethane(2×200 ml), the combined organic extracts were washed with water (200ml), dried (Na₂SO₄) and the solvent removed in vacuo at room temperatureto give an orange/brown oil which was dissolved in dry tetrahydrofuran(40.0 ml) and added dropwise to the stirred lithio acetonitrilereagent(52.19 mmol) in tetrahydrofuran at −70° C. TLC inspectionimmediately after the addition showed that the reaction was complete.Quenched with water (20.0 ml), diluted with ethyl acetate (300 ml),washed with brine (2×200 ml), dried (Na₂SO₄) and adsorbed onto silica(ca. 12.0 g). Column chromatography (ethyl acetate-light petroleum (b.p.40-60° C.), 1:4) gave the title compound as a pale yellow oil (4.17 g,78%). (Found: C, 67.62; H, 5.04; N, 5.94; Br, 17.60. C₂₆H₂₃BrN₂Orequires C, 67.98; H, 5.05; N, 6.10; Br, 17.39%); [α]_(D) ¹⁹ −138(c=0.010 gml^(−1 , CHCl) ₃); ν_(max) (thin film)/cm⁻¹ 3064, 2934, 2871,2246.5 (CN), 1575; δ_(H) (270 MHz) 1.55 (2H, m, 2×butyl 3-H); 2.23 (2H,t, 2×butyl 4-H, ³J_(4,3)=6.9 Hz); 2.30 (2H, m, 2×butyl 2-H); 5.17 (2H,q, CH₂ Ph, ²J=10.9 Hz); 6.35 (1H, dd, butyl 1-H, ³J_(1,2)=9.7,³J_(1,2)=5.8 Hz); 6.56 (1H, d, 3-H, ³J_(2,2)=3.3 Hz); 6.74 (1H, d, 6-H,J_(o)=7.9 Hz); 6.95 (1H, d, 4-H, J_(o)=7.9 Hz); 7.00 (1H, t, 5-H,J_(o)=7.9 Hz); 7.08 (1H, t, 5′-H, J_(o)=7.9 Hz); 7.14 (1H, d, 2-H,³J_(3,2)=3.3 Hz); 7.21 (1H, d, 6′-H, J_(o)=8.9 Hz); 7.25 (1H, t, 2′-H,J_(m)=1.1 Hz); 7.34 (1H, dd, 4′-H, J_(o)=8.4, J_(m)=1.5 Hz); 7.42 (5H,m, 5ArH). δ_(C) (67.8 MHz) 16.5 (butyl 3-C); 22.3 (butyl 4-C); 34.4(butyl 2-C); 58.8 (butyl 1-C); 70.6 (PhCH₂); 103.5 (indole 3-C); 104.1(indole 6-C); 114.2 (indole 4-C); 119.1 (CN); 120.2 (indole 5-C); 122.6(3′-C); 124.5 (indole 2-C); 125.0 (6′-C); 130.7 (1′-C); 136.5 (benzylipso-C); 144.2 (indole 7a-C); 147.0 (indole 7-C). The remaining signalslie between 128.2-130.6 ppm and cannot be assigned with any certainty;m/z 460.1, 458.1 (3.43, 3.32), 369.1, 367.1 (1.79, 1.66), 239.0, 237.0(7.01, 7.72), 171.0, 169.0 (26.03, 26.07), 143.1 (100), 132.1 (6.44),116.0 (9.37).

(J) (1S)-(+)-7-Benzyloxy-1-[1-(3-bromophenyl)-4-cyanobutyl]indole

The title compound was prepared from(3S)-(+)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ol by asequence analogous to that described above for the R-enantiomer. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)provided the title compound (51%) as a yellow oil; [α]_(D) ²⁰ +153(c=0.011 gml⁻¹, CHCl₃).

(k) (1R)-(−)-1-[1-(3-Bromophenyl)-4-cyanobutyl]-7-cyanomethoxyindole

The title compound was prepared from(1R)-(−)-7-benzyloxy-1-[1-(3-bromophenyl)-4-cyanobutyl]indole (4.34 g,9.45 mmol) by a sequence analogous to that described below for step (c)Example 4. Standard workup and column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compoundas a pale yellow oil (2.70 g, 70%). (Found: C, 61.60; H. 4.34; N, 10.29.C₂₁H₁₈BrN₃O requires C, 61.78; H, 4.44; N, 10.29%); [α]_(D) ²⁵ −127(c=0.008 gml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 3066.0, 2934.0, 2871.0,2247.0 (CN), 1594, 1572.0; δ_(H) (270 MHz) 1.66 (2H, m, 2×butyl 3-H);2.34 (2H, t, 2×butyl 4-H, ³J_(4,3)=6.9 Hz); 2.35 (2H, m, 2×butyl 2-H);4.78 (2H, s, OCH₂ CN); 6.18 (1H, dd, 1-H, ³J_(1,2)=8.9, ³J_(1,2′)=6.6Hz); 6.59 (1H, 3-H, ³J_(3,2)=3.3 Hz); 6.65 (1H, d, 6-H, J_(o)=7.6 Hz);7.01 (1H, t, 5-H, J_(o)=7.7 Hz); 7.12 (2H, m, 4-H, 6′-H); 7.20 (1H, d,2-H, ³J_(3,2)=3.3 Hz); 7.30 (3H, m, 2′-H, 4′-H, 5′-H). δ_(C) (67.8 MHz)16.8 (butyl 3-C); 22.4 (butyl 4-C); 34.5 (butyl 2-C); 53.6 (OCH₂CN);59.7 (butyl 1-C); 103.7 (indole 3-C); 104.4 (indole 6-C); 114.9 (OCH₂CN); 116.3 (indole 4-C); 119.1 (butyl CN); 120.0 (indole 5-C); 122.8(3′-C); 125.0 (indole 2-C); 125.3 (6′-C); 125.7 (indole 3a-C); 129.3(5′-C); 130.4 (4′-C); 130.8 (2′-C); 131.5 (11-C); 143.9 (indole 7a-C);144.0 (7-C).

(l) (1S)-(+)-1-[1-(3-Bromophenyl)-4-cyanobutyl]-7-cyanomethoxyindole

The title compound was prepared from(1S)-(+)-7-benzyloxy-1-[1-(3-bromophenyl)-4-cyanobutyl]indole by asequence analogous to that described above for the R-enantiomer. Columnchromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4)provided the title compound (39%) as a yellow oil; [α]_(D) ²⁰ +135(c=0.009 gml⁻¹, CHCl₃).

(m)(1R)-(−)-7-Chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-4-cyanobutyl]phenyl}ethenyl)quinoline

The title compound was prepared from(1R)-(−)-1-[1-(3-bromophenyl)-4-cyanobutyl]-7-cyanomethoxyindole by asequence analogous to that described below in step (d) of Example 4.Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.),1:4) provided the title compound (63%) as a grey/green oil. [α]_(D) ¹⁹−159 (c=0.00484 gml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 2245.5, 1607.5,1575.5; δ_(H) (270 MHz) 1.67 (2H, m, 2×3-H); 2.42 (2H, t, 2×4-H,³J_(4,3)=6.9 Hz); 2.42 (2H, m, 2×2-H); 4.83 (2H, s, OCH₂ CN); 6.28 (1H,dd, indole 1-H, ³J_(1,2)=8.9, ³J_(1,2′)=6.6 Hz); 6.61 (1H, d, indole3-H, ³J_(3,2)=3.3 Hz); 6.69 (1H, d, indole 6-H, J_(o)=7.9 Hz); 7.04 (1H,t, 5′-H, J_(o)=7.9 Hz); 7.17 (1H, d, indole 4-H, J_(o)=7.9 Hz);7.25-7.73 (10H, m, 10ArH); 8.09 (2H, m, 4-H, 8-H). δ_(C) (67.8 MHz) 16.9(butyl 3-C); 22.5 (butyl 4-C); 53.8 (OCH₂CN); 60.2 (butyl 1-C); 103.5(indole 3-C); 104.4 (indole 6-C); 115.1 (OCH₂ CN); 116.4 (indole 4-C);119.2 (CN); 119.7 (quinoline 3-C); 119.9 (indole 5-C); 135.2 (3′-C);135.5 (quinoline 7-C); 136.2 (quinoline 4-C); 136.8 (1′-C); 142.1(indole 7a-C); 144.1 (indole 7-C); 148.5 (quinoline 8a-C); 156.6(quinoline 2-C). The remaining signals lie between 125.5 to 134.5 ppm.

(n)Trans-(1S)-(+)-7-Chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-4-cyanobutyl]phenyl}ethenylquinoline

The title compound was prepared from(1S)-(+)-1-[1-(3-bromophenyl)-4-cyanobutyl]-7-cyanomethoxy indole (19b)by a sequence analogous to that described above for the R-enantiomer.Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.),1:4) provided the title compound (65%) as a yellow oil; [α]_(D) ²⁵ +157(c=0.007 gml⁻¹, CHCl₃).

(o)(1R)-(−)-7-Chloro-2-(2-{3-[1-(7-{1H-tetrazol-5-ylmethoxy}indol-1-yl)-4-(1H-tetrazol-5-yl)butyl]phenyl}ethenyl)quinoline

The title compound was prepared from(1R)-(−)-7-chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-4-cyanobutyl]phenyl}ethenyl)quinolineby a sequence analogous to that described below in step (e) of Example4. Filtration gave the crude title compound as a mustard yellow solid(>100%). HPLC separation showed that this material was ˜63% pure, whichtranslates to a 70% yield for the reaction. [α]_(D) ¹⁹ −126 (c=0.89mgml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 3406 (br, NH), 1635.5, 1608.5,1573.0; δ_(H) (270 MHz) 1.80 (2H, quintet, 2×butyl 2-H, ³J=7.8 Hz); 2.11(1H, m, butyl 3-H); 2.29 (1H, m, butyl 3-H); 2.90 (2H, t, 2×butyl 1-H,³J_(1,2)=7.3 Hz); 5.47 (2H, s, OCH₂ Tet); 6.40 (1H, t, butyl 4-H,³J_(4,3)=8.1 Hz); 6.49 (1H, d, indole 3-H, ³J_(3,2)=3.3 Hz); 6.83 (1H,d, indole 6-H, J_(o)=7.3 Hz); 6.92 (2H, m, 2×ArH); 7.16 (4H, m, 4×ArH);7.44 (4H, m, 4×ArH); 7.76 (1H, d, ArH, J_(o)=8.4 Hz); 7.87 (1H, d,quinoline 3-H, J_(o)=8.9 Hz); 7.90 (1H, d, quinoline 8-H, J_(m)=2.0 Hz);8.17 (1H, d, quinoline 4-H, J_(o)=8.9 Hz).

(p)(1S)-(+)-7-Chloro-2-(2-{3-[1-(7-{1H-tetrazol-5-ylmethoxy}indol-1-yl)-4-(1H-tetrazol-5-yl)butyl]phenyl}ethenyl)quinoline

The title compound was prepared from(1S)-(+)-7-chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-4-cyanobutyl]phenyl}ethenyl)quinoline (21b) by a sequence analogous to thatdescribed above for the R-enantiomer. Filtration gave the crude titlecompound as a mustard yellow solid.

EXAMPLE 4 Synthesis oftrans-(1R)-(−)-7-chloro-2-(2-{3-[1-(7-{1H-tetrazol-5-ylmethoxy}indol-1-yl)-3-(1H-tetrazol-5-yl)propyl]phenyl}ethenyl)quinoline(a) (3R)-3-(3-Bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ylmethanesulfonate

Methanesulfonyl chloride (0.20 ml, 2.61 mmnol) in dry dichloromethane(4.0 ml) was added dropwise to a stirred solution of(3R)-(−)(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.04 g,2.37 mmol prepared as in step (h) of Example 3) and triethylamine (0.73ml, 5.20 mmol) in dichloromethane (30.0 ml) at −10° C. (ice-MeOH). Themixture was stirred below 10° C. for 20 min, treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.44 mmol) in oneportion then heated under reflux for 2.5 h. The cooled one portion thenheated under reflux for 2.5 h. The cooled reaction mixture was adsorbedonto silica (ca. 5.0 g) and column chromatography (ethyl acetate-lightpetroleum (b.p. 40-60° C.), 1:4) gave the title compound as a pale greenoil (0.99 g, 81%). ν_(max) (thin film)/cm⁻¹ 3032.5, 2934.0, 1576.5,1523.0; δ_(H) (270 MHz) 2.55 (2H, m, 2×propyl 2-H); 2.60 (3H, s, SO₂CH₃); 3.98 (1H, m, 1×propyl 3-H); 4.14 (1H, m, 1×propyl 3-H); 5.11 (2H, q,CH₂ Ph, ²J=11.1 Hz); 6.56 (1H, m, propyl 1-H); 6.59 (1H, d, 3-H,³J_(3,2)=3.3 Hz); 6.73 (1H, dd, 6-H, J_(o)=7.6, J_(m)=0.7 Hz); 6.88 (1H,dd, 4-H, J_(o)=7.6, J_(m)=0.9 Hz); 7.00 (1H, t, 5-H, J_(o)=7.9 Hz); 7.06(1H, t, 5′-H, J_(o)=7.9 Hz); 7.21 (1H, d, 2-H, ³J_(2,3)=3.3 Hz); 7.24(1H, dd, 6′-H, J_(o)=7.9, Jm=1.0 Hz); 7.38 (7H, m, 7 ArH). δ_(C) (67.8MHz) 35.2 (propyl 2-C); 36.6 (SO₂ CH₃); 56.2 (propyl 3-C); 70.5 (PhCH₂);103.8 (indole 3-C); 104.3 (indole 6-C); 114.2 (indole 4-C); 120.4(indole 5-C); 122.6 (3′-C); 124.6 (indole 2-C); 130.8 (1′-C); 136.5(benzyl ipso-C); 143.9 (indole 7a-C); 146.6(indole 7-C). The remainingsignals lie between 128.1-130.6 ppm and cannot be assigned with anycertainty; m/z 514.8, 512.9 (3.05, 3.03, M⁺), 328.9, 326.8 (1.64, 1.79),293.8, 291.8 (2.83, 2.74), 197.8, 195.8 (99.25, 100), 170.8, 168.8(63.59, 67.93), 132.0 (8.98), 116.0 (27.78).

(b) (1R)-(−)-7-Benzyloxy-1-[1-(3-bromophenyl)-3-cyanopropyl]indole

A solution of(3R)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-ylmethanesulfonate (2.50 g, 4.86 mmol prepared as in Example 3, step (i))and tetrabutylammonium cyanide (1.96 g, 7.30 mmol) in dry acetonitrile(40.0 ml) under nitrogen was heated under reflux for 24 h. The cooledsolution was evaporated to yield an orange/brown oil which was taken upin ethyl acetate (200 ml), washed with water (3×100 ml), dried (Na₂SO₄)and the solvent removed in vacuo. Column chromatography (ethylacetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compoundas a pale yellow oil (1.60 g, 74%). [α]_(D) ¹⁹ −129 (c=0.005 gml⁻¹,CHCl₃); ν_(max) (thin film)/cm⁻¹ 3064, 3033, 2932, 2872, 2247 (CN),1575; δ_(H) (270 MHz) 2.10 (2H, m, 2×propyl 3-H); 2.38 (2H, m, 2×propyl2-H); 5.09 (2H, q, CH₂ Ph, ²J=10.9 Hz); 6.39 (1H, dd, propyl 1-H,³J_(1,2)=9.7, ³J_(1,2′)=5.8 Hz); 6.55 (1H, d, 3-H, ³J_(3,2)=3.3 Hz);6.70 (1H, d, 6-H, J_(o)=7.6 Hz); 6.83 (1H, d, 4-H, J_(o)=7.6 Hz); 7.00(2H, m, 5-H, 5′-H); 7.05 (1H, d, 2-H, ³J_(2,3)=3.0 Hz); 7.15 (1H, s,2′-H); 7.21 (1H, d, 6′-H, J_(o)=8.0 Hz); 7.30 (1H, d, 4′-H, J_(o)=8.6Hz); 7.38 (5H, m, 5ArH).

(c) (1R)-(−)-1-[1-(3-Bromophenyl)-3-cyanopropyl]-7-cyanomethoxyindole.General procedure for the debenzylation and subsequent cyanomethylationof 7-benzyloxyindoles

A 1.0 M solution of boron tribromide in dichloromethane (13.0 ml, 13.0mmol) was added dropwise over 20 min to a solution of(1R)-(−)-7-benzyloxy-1-[1-(3-bromophenyl)-3-cyanopropyl]indole (1.60 g,3.59 mmol) in dichloromethane (40.0 ml) at −75° C. under nitrogen. Theresulting orange/brown solution was stirred below −70° C. for anadditional 5 min, quenched with 2M aqueous hydrochloric acid (200 ml)and extracted with dichloromethane (3×200 ml). The combined organicextracts were washed with 2M hydrochloric (200 ml), dried (Na₂SO₄) andthe solvent removed in vacuo to yield a dark brown oil. This oil wasdissolved in butanone (40.0 ml) and added dropwise to a stirredrefluxing solution of bromoacetonitrile (1.30 ml, 17.96 mmol) andanhydrous potassium carbonate (13.6 g, 98.4 mmol) under nitrogen. Thebrown mixture was heated under reflux for 30 min, cooled to roomtemperature, filtered and the residue was washed with ethyl acetate (200ml). The organic washings were combined, washed with water (2×200 ml),dried (Na₂SO₄) and adsorbed onto a quantity of silica (ca. 6.0 g).Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.),1:4) gave the title compound as a pale yellow oil (1.00 g, 71%).C₂₀H₁₆BrN₃O requires C, 60.93; H, 4.10; N, 10.66; Br, 20.27%); [α]_(D)²⁸ −164 (c=0.009 gml⁻¹, CHCl₃); ν_(max) (thin film)/cm⁻¹ 3023.5, 2934.0,2247.0 (CN), 1594.0, 1576.0; δ_(H) (270 MHz) 2.34 (2H, m, 2×propyl 3-H);2.51 (2H, m, 2×propyl 2-H); 4.85 (2H, dd, OCH ₂CN, ²J=15.2 Hz); 6.36(1H, t, propyl 1-H, ³J_(1,2)=7.6 Hz); 6.58 (1H, d, Indole 3-H,³J_(3,2)=2.3 Hz); 6.72 (1H, d, Indole 6-H, J. =7.6 Hz); 7.01-7.41 (7H,m, 7ArH); δ_(C) (67.8 MHz) 14.7 (Propyl 2-C), 31.1 (Propyl 3-C), 53.6(OCH₂CN), 58.7 (Propyl 1-C), 104.3 (Indole 3-C), 104.7 (Indole 6-C),115.1 (CN), 116.4 (Indole 4-C), 118.7 (CN), 120.4 (Indole 5-C), 123.0(3′-C), 125.3 (Indole 2-C), 128.2 (6′-C), 129.0 (Indole 3a-C), 129.5(5′-C), 130.6 (4′-C), 131.3 (2′-C), 131.5 (1′-C), 142.4 (Indole 7a-C),144.0 (Indole 7-C); m/z 409.2, 407.3 (2.36, 2.54, M⁺), 341.1, 339.1(1.04, 1.06), 329.3 (1.68), 238.0, 236.0 (1.20, 1.30), 195.2 (8.62),172.1 (5.39), 171.0, 169.0 (1.59, 2,72), 132.1 (6,14), 116.1 (6.12),43.0 (100).

(d)Trans-(1R)-(−)-7-chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-3-cyanopropyl]phenyl}ethenyl)quinoline

A solution of(1R)-(−)-1-[1-(3-bromophenyl)-3-cyanopropyl]-7-cyanomethoxyindole (0.96g, 2.44 mmol) and 7-chloro-2-ethenylquinoline (0.51 mg, 2.69 mmol) inacetonitrile (4.0 ml) and triethylamine (4.0 ml) was placed in a 10.0 mlcapped bottle equipped with a pea stirrer. After degassing and flushingwith nitrogen, bisdiphenylphosphinopropane palladium dichloride (60 mg,122 μmol) was added in one portion and the mixture was heated at 100° Cfor 4 days. The cooled reaction mixture was adsorbed onto a quantity ofsilica (ca. 4.0 g) and column chromatography (ethyl acetate-lightpetroleum (b.p. 40-60° C.), 1:4) gave unreacted aryl bromide as anorange oil (0.21 g, 22%). Further elution gave the title compound as agrey/green oil (400 mg, 33%). [α]_(D) ¹⁹ −159 (c=0.005 gml⁻¹, CHCl₃);ν_(max) (thin film)/cm⁻¹ 2246.0, 1652.5, 1607.0, 1575.5, 1520.5;

(e)Trans-(1R)-(−)-7-chloro-2-(2-{3-[1-(7-(1H-tetrazol-5-ylmethoxy)indol-1-yl)-3-(1H-tetrazol-5-yl)propyl]phenyl}ethenyl)quinoline

A magnetically stirred solution of(1R)-(−)-7-chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-3-cyanopropyl]phenyl}ethenyl)quinoline(20) (0.30 g, 0.597 mmol) and tributyltin azide (0.79 g, 2.39 mmol) in1,2-dimethoxyethane (5.0 ml) was heated at 150° C. for 5 h during whichtime the DME solvent was allowed to boil off. The resulting dark brownmass was allowed to cool to room temperature, dissolved in 10% aceticacid in methanol (15.0 ml) and evaporated in vacuo to give a dark redoil. The red oil was dissolved in aqueous 2M NaOH_((aq)) (100 ml),washed with dichloromethane (2×70.0 ml), ethyl acetate (2×70.0 ml) andlight petroleum (b.p. 40-60° C.) (3×70.0 ml). Acidification of theaqueous phase with acetic acid yielded the title compound (70%) as anolive green solid which was collected by filtration. ν_(max) (thin film)/cm⁻¹ 3400 (br. OH), 1653.0, 1635.0, 1608.5, 1575.5; δ_(H) (270 MHz)2.35 (2H, m, 2×propyl 1-H), 2.64 (2H, m, 2×propyl 2-H); 4.90 (2H, s, OCH₂CN); 6.47 (1H, m, propyl 3-H); 6.61 (1H, m, indole 3-H); 6.75 (1H, m,indole 6-H); 7.03-7.70 (12H, m, 12×ArH); 8.06 (2H, m, quinoline 4-H,8-H). δ_(C) (67.8 MHz) 14.7 (propyl 2-C), 31.2 (propyl 1-C), 53.6(OCH₂CN) 59.1 (propyl 3-C), 104.0 (indole 3-C), 104.6 (indole 6-C),115.2 (CN), 116.3 (indole 4-C), 118.8 (CN), 119.7 (quinoline 3-C), 120.2(indole 5-C), 140.6 (indole 7a-C), 144.1 (indole 7-C), 148.5 (quinoline8a-C), 156.6 (quinoline 2-C). The remaining signals lie between 125.6and 137.1 ppm and cannot be assigned with any certainty.

What is claimed is:
 1. A composition comprising a compound of formula

substantially free of the anantiomer

wherein R¹ is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitrile,optionally protected carboxy, optionally protected tetrazolyl,trihalomethyl, hydroxy-C₁₋₄ alkyl, aldehyde, —CH₂Z, —CH═CH—Z or —CH₂CH₂Zwhere Z is optionally protected carboxy or optionally protectedtetrazolyl; R² is halo, nitrile, an optionally protected acid group or—CONR⁷R⁸ where R⁷ and R⁸ are hydrogen or C₁₋₄ alkyl; R⁴ is C₂₋₄ alkyl,or C₂₋₄ alkyl substituted by —CONR⁷R⁸ or an optionally protected acidgroup; R⁵ is

where W is —CH═CH—, —CH═N—, —N═CH—, —O— or —S—, R⁹ is hydrogen, halo,C₁₋₄ alkyl, C₁₋₄ alkoxy or trihalomethyl, and R¹⁰ is hydrogen, C₁₋₄alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl or C₁₋₄ akyl-C₃₋₆ cycloalkyl; R⁶ ishydrogen or C₁₋₄ alkyl; X is —O—(CH₂)_(n)CR¹¹R¹²—, —CR¹¹R¹²—,—CR¹¹R¹².(CH₂)_(n).CR¹³R¹⁴— or —CR¹¹═CR¹²— where R¹¹, R¹², R¹³ and R¹⁴are each hydrogen or C₁₋₄ alkyl, and n is 0, 1 or 2; and Y is—O—CR¹⁵R¹⁶—, —CR¹⁵═CR¹⁶— or —CR¹⁵R¹⁶.CR¹⁷R¹⁸— where R¹⁵, R¹⁶, R¹⁷ andR¹⁸ are each hydrogen or C₁₋₄ alkyl; or a salt thereof.
 2. A compositioncomprising a compound of formula

substantially free of the enantiomer

wherein R¹ is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitrile,optionally protected carboxy, optionally protected tetrazolyl,trihalomethyl, hydroxy-C₁₋₄ alkyl, aldehyde, —CH₂Z, —CH═CH—Z or —CH₂CH₂Zwhere Z is optionally protected carboxy or optionally protectedtetrazolyl; R² is halo, nitrile, an optionally protected acid group or—CONR⁷R⁸ where R⁷ and R⁸ are hydrogen or C₁₋₄ alkyl; R⁴ is C₂₋₄ alkyl,or C₂₋₄ alkyl substituted by —CONR⁷R⁸ or an optionally protected acidgroup; R⁵ is

where W is —CH═CH—, —CH═N—, —N═CH—, —O— or —S—, R⁹ is hydrogen, halo,C₁₋₄ alkyl, C₁₋₄ alkoxy or trihalomethyl, and R¹⁰ is hydrogen, C₁₋₄alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl or C₁₋₄ akyl-C₃₋₆ cycloalkyl; R⁶ ishydrogen or C₁₋₄ alkyl; X is —O—(CH₂)_(n)CR¹¹R¹²—, —CR¹¹R¹²—,—CR¹¹R¹².(CH₂)_(n).—CR¹³R¹⁴— or —CR¹¹═CR¹²— where R¹¹, R¹², R¹³ and R¹⁴are each hydrogen or C₁₋₄ alkyl, and n is 0, 1 or 2; and Y is—O—CR¹⁵R¹⁶—, —CR¹⁵═CR¹⁶— or —CR¹⁵R¹⁶.CR¹⁷R¹⁸—0 where R¹⁵, R¹⁶, R¹⁷ andR¹⁸ are each hydrogen or C₁₋₄ alkyl; or a salt thereof.
 3. A compoundhaving the formula IV:

wherein wherein R¹ is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitrile,optionally protected carboxy, optionally protected tetrazolyl,trihalomethyl, hydroxy-C₁₋₄ alkyl, aldehyde, —CH₂Z, —CH═CH—Z or —CH₂CH₂Zwhere Z is optionally protected carboxy or optionally protectedtetrazolyl; R² is halo, nitrile, an optionally protected acid group or—CONR⁷R⁸ where R⁷ and R⁸ are hydrogen or C₁₋₄ alkyl; R⁴ is C₂₋₄ alkyl,or C₂₋₄ alkyl substituted by —CONR⁷R⁸ or an optionally protected acidgroup; R⁵ is

where W is —CH═CH—, —CH═N—, —N═CH—, —O— or —S—, R⁹ is hydrogen, halo,C₁₋₄ alkyl, C₁₋₄ alkoxy or trihalomethyl, and R¹⁰ is hydrogen, C₁₋₄alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl or C₁₋₄ akyl-C₃₋₆ cycloalkyl; R⁶ ishydrogen or C₁₋₄ alkyl; X is —O—(CH₂)_(n)CR¹¹R¹²—, —CR¹¹R¹²—,—CR¹¹R¹².(CH₂)_(n).CR¹³R¹⁴— or —CR¹¹═CR¹²— where R¹¹, R¹², R¹³ and R¹⁴are each hydrogen or C₁₋₄ alkyl, and n is 0, 1 or 2; and Y is—O—CR¹⁵R¹⁶—, —CR¹⁵═CR¹⁶— or —CR¹⁵R¹⁶.CR¹⁷R¹⁸— where R¹⁵, R¹⁶, R¹⁷ andR¹⁸ are each hydrogen or C₁₋₄ alkyl; or a salt thereof.